Certain cis-imidazolines are antagonists of MDM2 and MDMX. They have utility as cancer chemotherapeutics by triggering or restoring apoptosis in cells with defective or inactive p53 tumor suppressor protein. This is explained for example, in U.S. Pat. Nos. 6,734,302; 6,617,346; and 7,705,007 and pre-grant publications US 2005/0282803 A1; US 2007/0129416 A1; and US 2013/0225603 A1. Cis-imidazolines such as Nutlin-3a are also being developed for killing senescent cells and treating senescence-associated conditions: US 2016/0339019 A1
Miyazaki et al., Bioorganic & Medicinal Chemistry Letters 23 (2013) 728-732 discusses lead optimization of novel p53-MDM2 interaction inhibitors possessing a dihydroimidazothiazole scaffold. Yu et al., Int. J. Mol. Sci. 2014, 15, 15741-15753, discusses the design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines. CN 103923067 B describes MDMX/MDM2 small molecule inhibitors, their preparation and use.
The biological activity of these cis-imidazolines typically resides in a single enantiomer. Several methods for the preparation of single-enantiomer versions of appropriately-substituted cis-imidazolines have been described. In WO2007/082805 and related patents, compounds are first prepared in racemic form, and then separated using chiral-HPLC strategies. US 2012/0088915 A1 describes an alternative approach in which a chiral catalyst is used to induce asymmetry into a key bond-forming step.
However, neither of these approaches is optimal for the large-scale preparation of chirally-pure cis-imidazolines of the type referred to above. Typical chiral HPLC-columns have a loading limit; to scale up a synthesis requires multiple purification runs, increasing the time required for synthesis, plus dramatically increasing the use of solvents and modifiers. The catalyst described in US 2012/0088915 A1 is itself prepared through a multi-step synthetic route; the overall synthesis of the final target requires a substantial number of additional chemical transformations.